1. Field of the Invention
The present invention relates to a combination of a CHK1 kinase inhibitor with a WEE1 kinase inhibitor and methods of use thereof.
2. Description of the State of Art
Checkpoint kinase 1 (“CHK1”) is a serine/threonine kinase. CHK1 regulates cell-cycle progression and is a main factor in DNA-damage response within a cell. CHK1 inhibitors have been shown to sensitize tumor cells to a variety of genotoxic agents, such as chemotherapy and radiation. (Tse, Archie N., et al., “Targeting Checkpoint Kinase 1 in Cancer Therapeutics.” Clin. Cancer Res. 13(7) (2007) 1955-1960). It has been observed that many tumors are deficient in the G1 DNA damage checkpoint pathway, resulting in the reliance on S and G2 checkpoints to repair DNA damage and survive. (Janetka, James W., et al., “Inhibitors of checkpoint kinases: From discovery to the clinic.” Drug Discovery & Development Vol. 10, No. 4 (2007) 473-486). The S and G2 checkpoints are regulated by CHK1. Inhibition of CHK1 has been shown to cancel the S and G2 checkpoints, thereby impairing DNA repair and resulting in increased tumor cell death. However, non-cancerous cells have a functioning G1 checkpoint, allowing for DNA repair and survival. A main target of CHK1 is the CDC25A phosphatase, which is an activator of cyclin dependent kinases (“CDKs”). When CHK1 phosphorylates CDC25A, CDC25A degradation is accelerated, which in turn slows down DNA replication and prevents entry into mitosis until the damage is repaired (Beck, Haldan, et al., “Regulators of cyclin dependent kinases are crucial for maintaining genome integrity in S phase.” J. Cell Biol. Vol. 188, No. 5 (2010) 629-638).
CHK1 inhibitors are known, see for example, International Publication WO 2009/004329, International Publication WO 2008/012635, International Publication WO 2007/090493, International Publication WO 2007/090494, International Publication WO 2006/106326, International Publication WO 2006/120573, International Publication WO 2005/103036, International Publication WO 2005/066163 and International Publication WO 03/028724.
CHK1 inhibitors include PF-00477736 (also known as PF-477736), AZD7762, XL844, IC-83, CHIR-124, PD-321852, LY2603618, LY2606368 and SCH 900776.
International Publication Number WO 2009/140320 describes compounds including (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (hereinafter “Compound 1”) and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ypisobutyramide (hereinafter “Compound 2”), (R)—N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (hereinafter “Compound 3”), (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide (hereinafter “Compound 4”), (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (hereinafter “Compound 5”), (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (hereinafter “Compound 6”), and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide (hereinafter “Compound 7”). Compounds 1, 2, 3, 4, 5, 6 and 7 (collectively the “'926 CHK1 Inhibitors”) are oral CHK1 inhibitors.
International Publication Number WO 2009/151589 describes CHK1 inhibitors (hereinafter “'589 Application CHK1 Inhibitors”). International Publication Number WO 2009/151598 describes CHK1 inhibitors (hereinafter “'598 Application CHK1 Inhibitors”).
Wee1-like protein kinase (“WEE1”) is a tyrosine kinase. WEE1 is inactivated in normal cells through phosphorylation and degradation during the M phase. WEE1 negatively regulates entry into mitosis by phosphorylating Cdc2 (Stathis, Anastaslos and Amit Oza, “Targeting Wee1-like Protein Kinase To Treat Cancer.” Drug News & Perspectives. 23(7) (2010) 425-429). Entry into mitosis is triggered by CDC25, which dephosphorylates Cdc2. WEE1 inhibition could result in abrogation of G2/M and uncontrolled entry into mitosis despite DNA damage. With the G2/M checkpoint inactive, cells could become more susceptible to DNA-damaging agents. Also healthy cells with a normal G1/S checkpoint may still survive.
WEE1 inhibitors are known, see for example, International Publication WO 2010/098367, International Publication WO 2010/067886, International Publication WO 2008/115742, International Publication WO 2008/115738, International Publication WO 2007/126122, International Publication WO 2007/126128, International Publication WO 2004/007499 and United States Patent Application Publication 2005/0037476.
WEE1 inhibitors include MK-1775, PD-166285 (also known as PD0166285) and PF-00120130.
There remains a need for treatments of diseases, particularly hyperproliferative diseases, such as cancer.